Christina Austin-Tse, Massachusetts General Hospital
Jan Halbritter, Children's Hospital Boston
Maimoona A. Zariwala, The University of North Carolina at Chapel Hill
Renée M. Gilberti, UConn Health
Heon Yung Gee, Children's Hospital Boston
Nathan Hellman, Massachusetts General Hospital
Narendra Pathak, Massachusetts General HospitalFollow
Yan Liu, Massachusetts General Hospital
Jennifer R. Panizzi, Massachusetts General Hospital
Ramila S. Patel-King, UConn Health
Douglas Tritschler, University of Minnesota Twin Cities
Raqual Bower, University of Minnesota Twin Cities
Eileen O'Toole, University of Colorado Boulder
Jonathan D. Porath, Children's Hospital Boston
Toby W. Hurd, University of Michigan, Ann Arbor
Moumita Chaki, University of Michigan, Ann Arbor
Katrina A. Diaz, University of Michigan, Ann Arbor
Stefan Kohl, Children's Hospital Boston
Svjetlana Lovric, Children's Hospital Boston
Daw Yang Hwang, Children's Hospital Boston
Daniela A. Braun, Children's Hospital Boston
Markus Schueler, Children's Hospital Boston
Rannar Airik, Children's Hospital Boston
Edgar A. Otto, University of Michigan, Ann Arbor
Margaret W. Leigh, UNC School of Medicine
Peadar G. Noone, UNC School of Medicine
Johnny L. Carson, UNC School of Medicine
Stephanie D. Davis, UNC School of Medicine
Jessica E. Pittman, UNC School of Medicine
Thomas W. Ferkol, Washington University School of Medicine in St. Louis
Jeffry J. Atkinson, Washington University School of Medicine in St. Louis
Kenneth N. Olivier, National Institute of Allergy and Infectious Diseases (NIAID)

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American Journal of Human Genetics


Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.





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©2013 by The American Society of Human Genetics.


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